This invention relates to the use of EP2 receptor subtype selective prostaglandin E2 agonists to augment bone mass including the prevention and treatment of skeletal disorders in mammals, including humans.
Osteoporosis is a systemic skeletal disorder, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecast to increase three-fold over the next 60 years, and one study estimates that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
In addition to hip fractures numbering approximately 250,000/year in the U.S., approximately, 20-25 million women and an increasing number of men have detectable vertebral fractures. Hip fracture is associated with a 12% mortality rate within the first two years and with a 30% rate of patients requiring nursing home care after the fracture. While this is already significant, the economic and medical consequences of convalescence due to slow or imperfect healing of these bone fractures is expected to increase, due to the aging of the general population.
There are currently two main types of pharmaceutical therapy for the treatment of osteoporosis and skeletal fractures. The first is the use of anti-resorptive compounds to inhibit the resorption of bone tissue and therefore prevent bone loss and reduce the incidence of skeletal fractures.
Estrogen is an example of an anti-resorptive agent. It is known that estrogen prevents post-menopausal bone loss and reduces skeletal fractures. However, estrogen fails to restore bone to the established osteoporotic skeleton. Furthermore, long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis.
A second type of pharmaceutical therapy for the treatment of osteoporosis and bone fractures is the use of anabolic agents to promote bone formation and increase bone mass. This class of agents are expected to restore bone to the established osteoporotic skeleton. There are a variety of natural prostaglandins (e.g., PGE, PGD and PGF) that are implicated in skeletal metabolism. PGE2 has been reported to stimulate bone formation, increase bone mass and bone strength in animal models of osteoporosis when administered locally or systemically. However, there are severe side effects which are associated with PGE2 such as diarrhea, gastrointestinal bleeding, decreased food consumption, dehydration, weight loss and decreased physical activity. Accordingly, PGE2 has not found widespread use in humans because of these side effects.
Recently, four different subtypes of PGE2 receptors (EP1, EP2, EP3 and EP4) have been cloned (Funk, C. D., et al., Cloning and Expression of a cDNA for the Human Prostaglandin E Receptor EP1 Subtype, Journal of Biological Chemistry, vol. 268, No. 35, pp. 26767-26772, 1993; Regan, J. W., et al., Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined EP2 Subtype, Molecular Pharmacology, vol. 46, pp. 213-220, 1994; Yang, J., et al., Cloning and Expression of the EP3-Subtype of Human Receptors for Prostaglandin E2, Biochemical Biophysical Research Communication, vol. 198, pp. 999-1006, 1994; Bastien, L., et al., Cloning, Functional Expression and Characterization of the Human Prostaglandin E2 Receptor EP2 Subtype, Journal Biological Chemistry, vol. 269, pp. 11873-11877, 1994). J. Bone Miner. Res. 1996, 11(supp.):S174 discussed the different subtyes of the PGE2 receptors. However, it is unclear whether one or more or these PGE2 receptor subtypes is selectively associated with bone anabolism of PGE2.
Skeletal disorders are highly prevalent diseases caused by nutrition deficiency, sex steroid deficiency, aging, trauma or other factors. All approved therapies and clinically advanced candidates including calcitonin, estrogen replacement therapy, bisphosphonates and estrogen agonists act to prevent bone loss by inhibiting bone resorption, but these agents cannot restore bone mass. Thus, there is significant medical need for anabolic agents that would increase bone mass and strength above a critical threshold in established osteoporotic patients, fractured patients, and other skeletal disorder patients.
This invention is directed to a method for augmenting bone mass and preventing bone loss in a mammal (including humans) comprising selectively agonizing, one of the prostaglandin E2 receptor subtypes, the EP2 receptor subtype by administering to a mammal a therapeutically effective amount of a selective EP2 receptor subtype agonist.
This invention is also directed to a method for treating (e.g., preventing) a mammal having a condition which presents with low bone mass comprising selectively agonizing the EP2 receptor subtype by administering to a mammal having a condition which presents with low bone mass a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to methods for treating (e.g., preventing) osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, prosthetic ingrowth, or inducing vertebral synostosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, prosthetic ingrowth or vertebral synostosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) osteoporosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from osteoporosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) osteotomy bone loss in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from an osteotomy bone loss a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) alveolar bone loss in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from an alveolar bone loss a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) bone loss associated with periodontitis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from bone loss associated with periodontitis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) childhood idiopathic bone loss in a child by selectively agonizing the EP2 receptor subtype by administering to a child suffering from childhood idiopathic bone loss a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) xe2x80x9csecondary osteoporosisxe2x80x9d, which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from xe2x80x9csecondary osteoporosisxe2x80x9d a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) glucocorticoid-induced osteoporosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from glucocorticoid-induced osteoporosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) hyperthyroidism-induced osteoporosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from hyperthyroidism-induced osteoporosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) immobilization-induced osteoporosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from immobilization-induced osteoporosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) heparin-induced osteoporosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from heparin-induced osteoporosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating (e.g., preventing) immunosuppressive-induced osteoporosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from immunosuppressive-induced osteoporosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for enhancing bone fracture healing in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from a bone fracture a therapeutically effective amount of a selective EP2 receptor subtype agonist. In one aspect of this invention the agonist is applied locally to the site of bone fracture.
Yet another aspect of this invention is directed to a method for enhancing bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal which has undergone facial reconstruction or maxillary reconstruction or mandibular reconstruction a therapeutically effective amount of a selective EP2 receptor subtype agonist. In one aspect of this invention the agonist is applied locally to the site of bone reconstruction.
Yet another aspect of this invention is directed to a method for treating prosthetic ingrowth in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from for prosthetic ingrowth a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for inducing vertebral synostosis in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal undergoing surgery for vertebral synostosis a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for enhancing long bone extension in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from an insufficiently sized long bone a therapeutically effective amount of a selective EP2 receptor subtype agonist.
Yet another aspect of this invention is directed to a method for treating a bone graft in a mammal (including a human being) by selectively agonizing the EP2 receptor subtype by administering to a mammal suffering from a bone graft a therapeutically effective amount of a selective EP2 receptor subtype agonist. In one aspect of this invention the agonist is applied locally to the site of the bone graft.
Preferably post-menopausal women and men over the age of 60 are treated.
In a preferred mode the EP2 agonist is at least 10 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
In a preferred mode the EP2 agonist is at least 25 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
In a preferred mode the EP2 agonist is at least 50 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
In a preferred mode the EP2 agonist is at least 75 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
In an especially preferred mode the EP2 agonist is at least 100 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
In an especially preferred mode the EP2 agonist is at least 150 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
In an especially preferred mode the EP2 agonist is at least 200 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
In an especially preferred mode the EP2 agonist is at least 250 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
In an especially preferred mode the EP2 agonist is at least 300 fold selective for the EP2 receptor subtype over the EP1, EP3 and EP4 receptor subtypes.
A preferred dosage is about 0.001 to 100 mg/kg/day of the selective EP2 agonist. An especially preferred dosage is about 0.01 to 50 mg/kg/day of the EP2 agonist.
Preferred selective EP2 agonists are compounds of Formula I 
or a pharmaceutically-acceptable salt or prodrug thereof
wherein either (i):
B is N;
A is (C1-C6)alkylsulfonyl, (C3-C7)cycloalkylsulfonyl, (C3-C7)cycloalkyl(C1-C6)alkylsulfonyl, said A moieties optionally mono-, di- or tri- substituted on carbon independently with hydroxy, (C1-C4)alkyl or halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C1-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-,
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C5)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other,
xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C5)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, or
xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-Nxe2x80x94(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, Nxe2x80x94(C1-C4)alkylenesulfonylamino, carboxamido, Nxe2x80x94(C1-C4)alkylenecarboxamido, carboxamidooxy, Nxe2x80x94(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is a bond, (C1-C8)alkylene, thio(C1-C4)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein Ar, Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3xe2x80x94C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono- Nxe2x80x94 or or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N- or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3 are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V is a bond or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
with the proviso that when K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy; or (ii):
B is N;
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri- substituted independently on carbon with hydroxy or halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-,
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C5)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other,
xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C5)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, or
xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-Nxe2x80x94(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, Nxe2x80x94(C1-C4)alkylenesulfonylamino, carboxamido, Nxe2x80x94(C1-C4)alkylenecarboxamido, carboxamidooxy, Nxe2x80x94(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is (C1-C8)alkylene, thio(C1-C4)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri- substituted independently with fluoro, methyl or chloro;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94A2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94A2 wherein Ar, Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are H, hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono- Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3 are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V is a bond or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
with the proviso that when K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy
and with the proviso that 6-[(3-Phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and its ethyl ester are not included or (iii):
B is C(H);
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri- substituted on carbon independently with hydroxy or halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said -(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C1-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-,
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C5)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other,
xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C5)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, or
xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-Nxe2x80x94(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, Nxe2x80x94(C1-C4)alkylenesulfonylamino, carboxamido, Nxe2x80x94(C1-C4)alkylenecarboxamido, carboxamidooxy, Nxe2x80x94(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4xe2x80x94oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is a bond, (C1-C8)alkylene, thio(C1-C4)alkylene, (C4-C7)cycloalkyl(C1-C6)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein Ar, Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are H, hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3 are optionally mono-, di- or tri-substituted independently on carbon with halo or hydroxy; and
V is a bond or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
with the proviso that when K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy.
A preferred group of compounds, designated the A Group, contains those compounds having the Formula I as shown above wherein
B is N;
A is (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl or (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, said A moieties optionally mono-, di-, or tri-substituted on carbon with fluoro;
X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
W is oxy, thio or sulfonyl;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
K is methylene or ethylene;
Ar, Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl or C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
R2 and R3 are chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
A group of compounds which is preferred among the A Group of compounds designated the B Group, contains those compounds wherein
A is (C1-C3)alkylsulfonyl;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl;
V is a bond or (C1-C2)alkylene;
R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C4)alkoxy, said (C1-C4)alkyl and (C1-C4)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro or fluoro.
Especially preferred compounds within the B Group of compounds are
7-[(2xe2x80x2-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino)-heptanoic acid,
7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoic acid, and
7-[(2xe2x80x2-Chloro-biphenyl4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid.
Especially preferred compounds within the B Group of compounds are compounds wherein
a. A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(2-hydroxymethylphenyl)phenyl;
b. A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(3-hydroxymethylthien-2-yl)phenyl; and
c. A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(2-chlorophenyl)phenyl.
A preferred group of compounds, designated the C Group, contains those compounds having the Formula I as shown above wherein
B is N;
A is (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl;
X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy;
W is oxy, thio or sulfonyl;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro;
M is xe2x80x94Ar, said xe2x80x94Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl or chromanyl;
R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted
independently with hydroxy, fluoro or chloro; and R2 and R3 are each independently hydroxy, halo, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, formyl, difluoromethoxy, trifluoromethoxy or carbamoyl.
It is especially preferred for Group C compounds that K is not optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro.
A group of compounds which is preferred among the C Group of compounds, designated the D Group, contains those compounds wherein
K is methylene;
A is (C1-C3)alkylsulfonyl;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein xe2x80x94Ar is substituted with at least R1;
R1 is (C1-C7)alkyl or (C1-C5)alkoxy, said (C1-C7)alkyl or (C1-C5)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
Especially preferred among the D Group of compounds are
7-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino]-heptanoic acid,
7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid,
7-{[5-(1-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoic acid and
(3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid.
A group of compounds which is preferred among the D Group of compounds, designated the E Group, contains those compounds wherein
Q is xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-; and
W is oxy.
A group of compounds which is preferred among the D Group of compounds, designated the F Group, contains those compounds wherein
Q is xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with from one to four fluorines.
Especially preferred compounds among the F Group of compounds are compounds wherein
a.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(1-hydroxy-n-hexylene-1-yl)phenyl;
b.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(n-butylene-1-yl)phenyl; and
c.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 5-(1-hydroxy-n-hexylene-1-yl)thien-2-yl.
A group of compounds which is preferred among the D Group of compounds, designated the G Group, contains those compounds wherein
Q is xe2x80x94Xxe2x80x94(C1-C5)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the H Group, contains those compounds wherein
Q is xe2x80x94(C1-C5)alkylene-Xxe2x80x94; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the I Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
An especially preferred compound within the I Group of compounds is a compound wherein
A is methylsulfonyl;
Q is 3-methylenephenylmethyl;
Z is carboxyl;
K is methylene; and
M is 4-(n-butylene-1-yl)phenyl.
A group of compounds which is preferred among the D Group of compounds, designated the J Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the D Group of compounds, designated the K Group, contains those compounds wherein
Q is xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the D Group of compounds, designated the L Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the M Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl or thienyl.
A group of compounds which is preferred among the D Group of compounds, designated the N Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the O Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the P Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
A group of compounds which is preferred among the D Group of compounds designated the Q Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the C Group of compounds designated the R Group, contains those compounds wherein
A is (C1-C3)alkylsulfonyl;
K is (C1-C8)alkylene;
xe2x80x94Ar is phenyl, thiazolyl, pyridyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxine, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
Preferred compounds among the R Group are
7-{[3-(3-Chloro-phenyl)-propyl)-methanesulfonyl-amino}-heptanoic acid,
7-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid and
5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid.
A group of compounds which is preferred among the R Group of compounds, designated the S Group, contains those compounds wherein
Q is xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-; and
W is oxy.
A group of compounds which is preferred among the R Group of compounds, designated the T Group, contains those compounds wherein
Q is xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with from one to four fluorines.
Especially preferred compounds among the T Group are compounds wherein
a.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is propylene; and
M is 3-chlorophenyl; and
b.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is propylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the R Group of compounds, designated the U Group, contains those compounds wherein
Q is xe2x80x94Xxe2x80x94(C1-C5)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the V Group, contains those compounds wherein
Q is xe2x80x94(C1-C5)alkylene-Xxe2x80x94; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
An especially preferred compound among the V group is a compound wherein
A is methylsulfonyl;
Qxe2x80x94Z is 3-(2-carboxylthien-5-yl)-n-propylene
K is propylene; and
M is 3-chlorophenyl.
A group of compounds which is preferred among the R Group of compounds, designated the W Group, contains those compounds wherein
Q is -(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the X Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the R Group of compounds, designated the Y Group, contains those compounds wherein
Q is xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the R Group of compounds, designated the Z Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94( C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the A1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl or thienyl.
A group of compounds which is preferred among the R Group of compounds, designated the B1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the C1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94( C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the D1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
A group of compounds which is preferred among the R Group of compounds, designated the E1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the C Group of compounds, designated the F1 Group, contains those compounds wherein
A is (C1-C3)alkylsulfonyl;
K is oxy(C1-C4)alkylene;
xe2x80x94Ar is phenyl, thienyl, thiazolyl, pyridyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and
R1, R2 and R are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
Especially preferred compounds within the F1 Group are
7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}heptanoic acid,
5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid and
N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1 H-tetrazol-5-yl)-hexyl]-methanesulfonamide.
A group of compounds which is preferred among the F1 Group of compounds, designated the G1 group, contains those compounds wherein
Q is xe2x80x94(C2-C6)alkylene-Wxe2x80x94( C1-C3)alkylene-; and
W is oxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the H1 Group, contains those compounds wherein
Q is xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with from one to four fluorines.
An especially preferred compound among the H1 group of compounds is a compound wherein
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is oxyethylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the F1 Group of compounds, designated the 11 Group, contains those compounds wherein
Q is xe2x80x94Xxe2x80x94(C1-C5)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the J1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C5)alkylene-Xxe2x80x94; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
An especially preferred compound among the J1 group is a compound wherein
A is methylsulfonyl;
Qxe2x80x94Z is 3-(2-carboxylthien-5-yl)-n-propylene;
K is oxyethylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the F1 Group of compounds, designated the K1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the L1 Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the M1 Group, contains those compounds wherein
Q is xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94( C1-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the N1 Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the O1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl or thienyl.
A group of compounds which is preferred among the F1 Group of compounds, designated the P1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the Q1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94( C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the R1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
A group of compounds which is preferred among the F1 Group of compounds, designated the S1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the C1 Group of compounds, designated the T1 Group, contains those compounds wherein
A is (C1-C3)alkylsulfonyl;
K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated;
xe2x80x94Ar is phenyl, thienyl, thiazolyl, pyridyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
Especially preferred compounds among the T1 Group are
Trans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-acetic acid,
Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazolyl-5-yl)-hexyl]-methanesulfonamide,
Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid and
Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid.
A group of compounds which is preferred among the T1 Group of compounds, designated the U1 Group, contains those compounds wherein
Q is xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-; and
W is oxy.
An especially preferred compound among the U1 group is a compound wherein
A is methylsulfonyl;
Q is methyloxy-n-butylene;
Z is carboxyl;
K is trans-2-n-propenylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the T1 Group of compounds, designated the V1 Group, contains those compounds wherein
Q is xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with from one to four fluorines.
A preferred compound among the V1 group of compound is a compound herein
A is methylsulfonyl;
Q is n-hexylene;
Z is 5-(1H-tetrazolyl);
K is trans-2-n-propeneylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the T1 Group of compounds, designated the W1 Group, contains those compounds wherein
Q is xe2x80x94Xxe2x80x94(C1-C5)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the X1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C5)alkylene-Xxe2x80x94; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A preferred compound among the X1 Group is a compound wherein
A is methylsulfonyl;
Qxe2x80x94Z is 3-(2-carboxylthien-5-yl)-n-propylene;
K is trans-2-n-propeneylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the T1 Group of compounds, designated the Y1 Group, contains those compounds wherein
Q is -(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the Z1 Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the A2 Group, contains those compounds wherein
Q is xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94( C1-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the B2 Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the C2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl or thienyl.
A group of compounds which is preferred among the T1 Group of compounds, designated the D2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the E2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the F2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
A group of compounds which is preferred among the T1 Group of compounds, designated the G2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A preferred group of compounds, designated the H2 Group, contains those compounds having the Formula I as shown above wherein
B is N;
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri- substituted on carbon independently with hydroxy or halo;
X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
W is oxy, thio or sulfonyl;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro;
Ar is (C5-C7)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, or chromanyl;
Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
R1 is halo, (C0-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
R2 and R3 are each independently hydroxy, halo, difluoromethoxy, trifluoromethoxy, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, formyl or carbamoyl.
It is especially preferred for the H2 Group that K is not optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro.
A group of compounds which is preferred among the H2 Group of compounds, designated the 12 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
K is methylene or ethylene;
M is xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl;
V is a bond or (C1-C2)alkylene;
R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C6)alkoxy, said (C1-C4)alkyl) and (C1-C6)alkoxy optionally mono-, di-or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro or fluoro.
A group of compounds which is preferred among the H2 Group of compounds, designated the J2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted independently on carbon with hydroxy or halo;
K is methylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein xe2x80x94Ar is substituted with at least R1;
R1 is (C1-C7)alkyl or (C1-C5)alkoxy, said (C1-C7)alkyl or (C1-C5)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
A group of compounds which is preferred among the H2 Group of compounds, designated the K2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
K is (C1-C8)alkylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said -(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3xe2x80x94dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A group of compounds which is preferred among the H2 Group of compounds, designated the L2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
K is oxy(C1-C4)alkylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A group of compounds which is preferred among the H2 Group of compounds, designated the M2 Group, contains those compounds wherein
A is (C3-C6)alkanoyl said (C3-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A preferred group of compounds, designated the N2 Group, contains those compounds having the Formula I as shown above wherein
B is C(H);
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri- substituted on carbon independently with hydroxy or halo;
X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
W is oxy, thio or sulfonyl;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro;
Ar is (C5-C7)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, or chromanyl;
Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
R2 and R3 are each independently hydroxy, halo, difluoromethoxy, trifluoromethoxy, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, formyl or carbamoyl.
It is especially preferred for Group N2 that K is not optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro.
A group of compounds which is preferred among the N2 Group of compounds, designated the O2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri- substituted on carbon independently with halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
K is methylene or ethylene;
M is xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl;
V is a bond or (C1-C2)alkylene;
R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C4)alkoxy, said (C1-C4)alkyl and (C1-C4)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro or fluoro.
A group of compounds which is preferred among the N2 Group of compounds, designated the P2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri- substituted on carbon independently with hydroxy or halo;
K is methylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein xe2x80x94Ar is substituted with at least R1;
R1 is (C1-C7)alkyl or (C1-C6)alkoxy, said (C1-C7)alkyl or (C1-C6)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
A group of compounds which is preferred among the N2 Group of compounds, designated the Q2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri- substituted on carbon independently with halo;
K is (C1-C8)alkylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A group of compounds which is preferred among the N2 Group of compounds, designated the R2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl said A optionally mono-, di- or tri- substituted on carbon independently with halo;
K is oxy(C1-C4)alkylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A group of compounds which is preferred among the N2 Group of compounds, designated the S2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri- substituted on carbon independently with halo;
K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
An especially preferred compound of the J2 Group of compounds is a compound wherein
A is propanoyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(n-1-hydroxylhexyl)phenyl.
An especially preferred compound among the H1 Group of compounds is a compound wherein
A is methylsulfonyl;
Q is n-hexylene;
Z is 5-(1H-tetrazolyl);
K is oxyethyl; and
M is 3,5-dichlorophenyl.
An especially preferred compound among the Y1 Group of compounds is a compound wherein
A is methylsulfonyl;
Q is 3-methylenephenylmethyl;
Z is carboxyl;
K is trans-2-n-propenylene; and
M is 3,5-dichlorophenyl.
An especially preferred group of compounds is
(3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid;
7-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid;
7-[(4-Hydroxy-nonyl)-methanesulfonyl-amino]-heptanoic acid;
7-[(2xe2x80x2-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid;
7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid;
7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid;
5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid;
Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid; or
N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.
A preferred dosage is about 0.001 to 100 mg/kg/day of the Formula I compound. An especially preferred dosage is about 0.01 to 50 mg/kg/day of the Formula I compound.
By selectively agonizing the EP2 receptor subtype is meant selectively binding to the EP2 receptor subtype preferentially (by at least 5 fold) over the EP1, EP3 and EP4 and interacting with the EP2 receptor resulting in increased cyclic AMP production.
By selective EP2 agonist is meant a compound that binds to the EP2 receptor preferentially (by at least 5 fold) over the EP1, EP3, EP4. In addition, a selective EP2 agonist binds and interacts with the EP2 receptor resulting in increased cyclic AMP production.
The phrase xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d refers to a condition where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization xe2x80x9cAssessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843xe2x80x9d. Included in xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d are primary and secondary osteoporosis. Secondary osteoporosis includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis and immunosuppressive-induced osteoporosis. Also included is periodontal disease, alveolar bone loss, osteotomy bone loss and childhood idiopathic bone loss. The xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d also includes long term complications of osteoporosis such as curvature of the spine, loss of height, prosthetic surgery.
The phrase xe2x80x9ccondition which presents with low bone massxe2x80x9d also refers to a mammal known to have a significantly higher than average chance of developing such diseases as are described above including osteoporosis (e.g., post-menopausal women, men over the age of 60.
Other bone mass augmenting or enhancing uses include increasing the bone fracture healing rate, enhancing the rate of successful bone grafts, bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction, prosthetic ingrowth, vertebral synostosis or long bone extension.
Those skilled in the art will recognize that the term bone mass actually refers to bone mass per unit area which is sometimes (although not strictly correctly) referred to as bone mineral density.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors, which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the Formula I compounds include but are not limited to substituents wherein the Z moiety is independently carboxyl and the free hydrogen is replaced by (C1-C4)alkyl, (C2-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton4-yl, di-N,Nxe2x80x94(C1-C2)alkylamino(C2-C3)alkyl (such as b-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
By alkylene is meant saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons (e.g., methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene).
By halo is meant chloro, bromo, iodo, or fluoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentyl, tertiary pentyl, hexoxy, isohexoxy, heptoxy and octoxy.
As used herein the term mono-N- or di-N,Nxe2x80x94(C1-Cx)alkyl . . . refers to the (C1-Cx)alkyl moiety taken independently when it is di-N,Nxe2x80x94(C1-Cx)alkyl . . . (x refers to integers).
Unless otherwise stated the xe2x80x9cMxe2x80x9d moieties defined above are optionally substituted (e.g., the mere listing of a substituent such as R1 in a subgenus or dependent claim does not mean that M is always substituted with the R1 moiety unless it is stated that the M moiety is substituted with R1.
It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate, through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or for example, a trivalent nitrogen atom. For example, the term xe2x80x9cpyridylxe2x80x9d means 2-, 3-, or 4-pyridyl, the term xe2x80x9cthienylxe2x80x9d means 2-, or 3-thienyl, and so forth.
The expression xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. The expression also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions xe2x80x9creaction-inert solventxe2x80x9d and xe2x80x9cinert solventxe2x80x9d refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The parenthetical negative or positive sign used herein in the nomenclature denotes the direction plane polarized light is rotated by the particular stereoisomer.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates of the compounds of this invention are also included.
The chemist of ordinary skill will recognize that certain combinations of heteroatom-containing substituents listed in this invention define compounds which will be less stable under physiological conditions (e.g., those containing acetal or aminal linkages). Accordingly, such compounds are less preferred.
DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediamine tetraacetic acid.
The methods of this invention result in bone formation resulting in decreased fracture rates. This invention makes a significant contribution to the art by providing compounds and methods that increase bone formation resulting in prevention, retardation, and/or regression of osteoporosis and related bone disorders.